Linezolid

1 INDICATIONS AND USAGE Linezolid injection is an oxazolidinone-class antibacterial indicated in adults and children for the treatment of the following infections caused by susceptible Gram-positive bacteria: Nosocomial pneumonia ( 1.1 ); Community-acquired pneumonia ( 1.2 ); Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis ( 1.3 ); Uncomplicated skin and skin structure infections ( 1.4 ); Vancomycin-resistant Enterococcus faecium infections. ( 1.5 ) Limitations of Use ( 1.6 ): Linezolid injection is not indicated for the treatment of Gram-negative infections. The safety and efficacy of Linezolid injection formulations given for longer than 28 days have not been evaluated in controlled clinical trials. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid injection formulations and other antibacterial drugs, Linezolid injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.7 ) 1.1 Nosocomial Pneumonia Linezolid injection is indicated for the treatment of nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates) or Streptococcus pneumoniae [ see Clinical Studies (14) ]. 1.2 Community-acquired Pneumonia Linezolid injection is indicated for the treatment of community-acquired pneumonia caused by Streptococcus pneumoniae , including cases with concurrent bacteremia, or Staphylococcus aureus (methicillin-susceptible isolates only) [ see Clinical Studies (14) ]. 1.3 Complicated Skin and Skin Structure Infections Linezolid injection is indicated for the treatment of complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis , caused by Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus pyogenes , or Streptococcus agalactiae . Linezolid injection has not been studied in the treatment of decubitus ulcers [ see Clinical Studies (14) ]. 1.4 Uncomplicated Skin and Skin Structure Infections Linezolid injection is indicated for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes [ see Clinical Studies (14) ]. 1.5 Vancomycin-resistant Enterococcus faecium Infections Linezolid injection is indicated for the treatment of vancomycin-resistant Enterococcus faecium infections, including cases with concurrent bacteremia [ see Clinical Studies (14) ]. 1.6 Limitations of Use Linezolid injection is not indicated for the treatment of Gram-negative infections. It is critical that specific Gram-negative therapy be initiated immediately if a concomitant Gram-negative pathogen is documented or suspected [ see Warnings and Precautions (5.4) ]. The safety and efficacy of Linezolid injection formulations given for longer than 28 days have not been evaluated in controlled clinical trials [ see Clinical Studies (14) ]. 1.7 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Linezolid injection and other antibacterial drugs, Linezolid injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION Infection Dosage, Route, and Frequency of Administration Duration (days) Pediatric Patients (Birth through 11 years of Age) Adults and Adolescents (12 years and Older) Nosocomial pneumonia 10 mg/kg intravenous or oral every 8 hours 600 mg intravenous or oral every 12 hours 10 to 14 Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia 10 mg/kg intravenous or oral every 8 hours 600 mg intravenous or oral every 12 hours 14 to 28 Uncomplicated skin and skin structure infections less than 5 yrs: 10 mg/kg oral every 8 hours 5-11 yrs: 10 mg/kg oral every 12 hours Adults: 400 mg oral every 12 hours Adolescents: 600 mg oral every 12 hours 10 to 14 2.1 General Dosage and Administration The recommended dosage for linezolid injection formulations for the treatment of infections is described in Table 1. Table 1. Dosage Guidelines for Linezolid Injection Infection Due to the designated pathogens [ see Indications and Usage (1) ] Dosage, Route and Frequency of Administration Recommended Duration of Treatment (consecutive days) Pediatric Patients Neonates less than 7 days: Most pre-term neonates less than 7 days of age (gestational age less than 34 weeks) have lower systemic linezolid clearance values and larger AUC values than many full-term neonates and older infants. These neonates should be initiated with a dosing regimen of 10 mg/kg every 12 hours. Consideration may be given to the use of 10 mg/kg every 8 hours regimen in neonates with a sub-optimal clinical response. All neonatal patients should receive 10 mg/kg every 8 hours by 7 days of life [ see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ]. (Birth through 11 Years of Age) Adults and Adolescents (12 Years and Older) Nosocomial pneumonia 10 mg/kg intravenously or oral Oral dosing using either linezolid tablets or linezolid for oral suspension [ see How Supplied/Storage and Handling (16) ] every 8 hours 600 mg intravenously or oral every 12 hours 10 to 14 Community-acquired pneumonia, including concurrent bacteremia Complicated skin and skin structure infections Vancomycin-resistant Enterococcus faecium infections, including concurrent bacteremia 10 mg/kg intravenously or oral every 8 hours 600 mg intravenously or oral every 12 hours 14 to 28 Uncomplicated skin and skin structure infections less than 5 yrs: 10 mg/kg oral every 8 hours 5-11 yrs: 10 mg/kg oral every 12 hours Adults: 400 mg oral every 12 hours Adolescents: 600 mg oral every 12 hours 10 to 14 No dose adjustment is necessary when switching from intravenous to oral administration. 2.2 Intravenous Administration Linezolid injection is supplied in single-dose, ready-to-use infusion bags. Parenteral drug products should be inspected visually for particulate matter prior to administration. Check for minute leaks by firmly squeezing the bag. If leaks are detected, discard the solution, as sterility may be impaired. Keep the infusion bags in the overwrap until ready to use. Store at room temperature. Protect from freezing. Linezolid injection may exhibit a yellow color that can intensify over time without adversely affecting potency. Linezolid injection should be administered by intravenous infusion over a period of 30 to 120 minutes. Do not use this intravenous infusion bag in series connections . Additives should not be introduced into this solution. If linezolid injection is to be given concomitantly with another drug, each drug should be given separately in accordance with the recommended dosage and route of administration for each product. Discard unused portion. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of linezolid injection with an infusion solution compatible with linezolid injection and with any other drug(s) administered via this common line…

5 WARNINGS AND PRECAUTIONS Myelosuppression: Monitor complete blood counts weekly. Thrombocytopenia has been reported more often in patients with severe renal and in patients with moderate to severe hepatic impairment. Consider discontinuation in patients who develop or have worsening myelosuppression. ( 5.1 ) Peripheral and Optic Neuropathy: Reported primarily in patients treated for longer than 28 days. If patients experience symptoms of visual impairment, prompt ophthalmic evaluation is recommended. ( 5.2 ) Serotonin Syndrome: Monitor patients taking serotonergic agents, including antidepressants and opioids, for signs of serotonin syndrome. Patients taking serotonergic antidepressants should receive linezolid injection only if no other therapies are available. Discontinue serotonergic antidepressants and monitor patients for signs and symptoms of both serotonin syndrome and antidepressant discontinuation. ( 5.3 ) A mortality imbalance was seen in an investigational study in linezolid-treated patients with catheter-related bloodstream infections. ( 5.4 ) Clostridiodes difficile -Associated Diarrhea: Evaluate if diarrhea occurs. ( 5.5 ) Potential interactions producing elevation of blood pressure: monitor blood pressure. ( 5.6 ) Rhabdomyolysis: If signs or symptoms of rhabdomyolysis are observed, discontinue linezolid injection and initiate appropriate therapy. ( 5.9 ) Hypoglycemia: Postmarketing cases of symptomatic hypoglycemia have been reported in patients with diabetes mellitus receiving insulin or oral hypoglycemic agents. ( 5.10 ) Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Monitor serum sodium levels regularly in patients at risk of hyponatremia and/or SIADH. ( 5.11 ) 5.1 Myelosuppression Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in patients receiving linezolid. In cases where the outcome is known, when linezolid was discontinued, the affected hematologic parameters have risen toward pretreatment levels. Thrombocytopenia has been reported more often in patients with severe renal impairment, whether or not on dialysis, and in patients with moderate to severe hepatic impairment. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those with severe renal impairment or moderate to severe hepatic impairment, those receiving concomitant drugs that produce bone marrow suppression, or those with a chronic infection who have received previous or concomitant antibacterial drug therapy. Discontinuation of therapy with linezolid should be considered in patients who develop or have worsening myelosuppression [ see Adverse Reactions ( 6.2 ) ]. 5.2 Peripheral and Optic Neuropathy Peripheral and optic neuropathies have been reported in patients treated with linezolid injection, primarily in those patients treated for longer than the maximum recommended duration of 28 days. In cases of optic neuropathy that progressed to loss of vision, patients were treated for extended periods beyond the maximum recommended duration. Visual blurring has been reported in some patients treated with linezolid injection for less than 28 days. Peripheral and optic neuropathy has also been reported in children. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, blurred vision, or visual field defect, prompt ophthalmic evaluation is recommended. Visual function should be monitored in all patients taking linezolid injection for extended periods (≥ 3 months) and in all patients reporting new visual symptoms regardless of length of therapy with linezolid injection. If peripheral or optic neuropathy occurs, the continued use of linezolid injection in these patients should be weighed against the potential risks. 5.3 Serotonin Syndrome Spontaneous reports of…

4 CONTRAINDICATIONS Known hypersensitivity to linezolid or any of the other product components. ( 4.1 ) Patients taking any monoamine oxidase inhibitors (MAOI) or within two weeks of taking an MAOI. ( 4.2 ) 4.1 Hypersensitivity Linezolid injection formulations are contraindicated for use in patients who have known hypersensitivity to linezolid or any of the other product components. 4.2 Monoamine Oxidase Inhibitors Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product.

7 DRUG INTERACTIONS Monoamine oxidase inhibitors and potential for interaction with adrenergic and serotonergic agents. ( 4.2 , 5.3 , 5.6 , 7 , 12.3 ) 7.1 Monoamine Oxidase Inhibitors Linezolid is a reversible, nonselective inhibitor of monoamine oxidase [ see Contraindications (4.2) and Clinical Pharmacology (12.3) ]. 7.2 Adrenergic and Serotonergic Agents Linezolid has the potential for interaction with adrenergic and serotonergic agents [ see Warnings and Precautions (5.3 , 5.6) and Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Available data from published and postmarketing case reports with linezolid use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. When administered during organogenesis, linezolid did not cause malformations in mice, rats, or rabbits at maternal exposure levels approximately 6.5 times (mice), equivalent to (rats), or 0.06 times (rabbits) the clinical therapeutic exposure, based on AUCs. However, embryo-fetal lethality was observed in mice at 6.5 times the estimated human exposure. When female rats were dosed during organogenesis through lactation, postnatal survival of pups was decreased at doses approximately equivalent to the estimated human exposure based on AUCs ( see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In mice, embryo-fetal toxicities were observed only at doses that caused maternal toxicity (clinical signs and reduced body weight gain). An oral dose of 450 mg/kg/day given from Gestation Day (GD) 6-16 (6.5 times the estimated human exposure based on AUCs) correlated with increased postimplantational embryo death, including total litter loss, decreased fetal body weights, and an increased incidence of costal cartilage fusion. Neither maternal nor embryo-fetal toxicities were observed at doses up to 150 mg/kg/day. Fetal malformations were not observed. In rats, fetal toxicity was observed at 15 and 50 mg/kg/day administered orally from GD 6-17 (exposures 0.22 times to approximately equivalent to the estimated human exposure, respectively, based on AUCs). The effects consisted of decreased fetal body weights and reduced ossification of sternebrae, a finding often seen in association with decreased fetal body weights. Fetal malformations were not observed. Maternal toxicity, in the form of reduced body weight gain, was seen at 50 mg/kg/day. In rabbits, reduced fetal body weight occurred only in the presence of maternal toxicity (clinical signs, reduced body weight gain and food consumption) when administered at an oral dose of 15 mg/kg/day given from GD 6-20 (0.06 times the estimated human exposure based on AUCs). Fetal malformations were not observed. When female rats were treated with 50 mg/kg/day (approximately equivalent to the estimated human exposure based on AUCs) of linezolid during pregnancy and lactation (GD 6 through Lactation Day 20), survival of pups was decreased on postnatal days 1 to 4. Male and female pups permitted to mature to reproductive age, when mated, showed an increase in preimplantation loss.

8.3 Females and Males of Reproductive Potential Infertility Males Based on findings from studies in rats, Linezolid injection may reversibly impair fertility in male patients [ see Nonclinical Toxicology (13.1) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [ see Warnings and Precautions (5.1) ] Peripheral and Optic Neuropathy [ see Warnings and Precautions (5.2) ] Serotonin Syndrome [ see Warnings and Precautions (5.3) ] Clostridioides difficile -Associated Diarrhea [ see Warnings and Precautions (5.5) ] Lactic Acidosis [ see Warnings and Precautions (5.7) ] Convulsions [ see Warnings and Precautions (5.8) ] Rhabdomyolysis [ see Warnings and Precautions (5.9) ] Hypoglycemia [ see Warnings and Precautions (5.10) ] Hyponatremia and/or Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) [ see Warnings and Precautions (5.11) ] Most common adverse reactions (>5% of adult and/or pediatric patients treated with linezolid injection) include: diarrhea, vomiting, headache, nausea, and anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The safety of linezolid formulations was evaluated in 2,046 adult patients enrolled in seven Phase 3 comparator-controlled clinical trials, who were treated for up to 28 days. Of the patients treated for uncomplicated skin and skin structure infections (uSSSIs), 25.4% of linezolid-treated and 19.6% of comparator-treated patients experienced at least one drug-related adverse event. For all other indications, 20.4% of linezolid-treated and 14.3% of comparator-treated patients experienced at least one drug-related adverse event. Table 2 shows the incidence of all-causality, treatment-emergent adverse reactions reported in at least 1% of adult patients in these trials by dose of linezolid. Table 2. Incidence (%) of Treatment-Emergent Adverse Reactions Occurring in >1% of Adult Patients Treated with Linezolid in Comparator-Controlled Clinical Trials ADVERSE REACTIONS Uncomplicated Skin and Skin Structure Infections All Other Indications Linezolid 400 mg by mouth every 12 hours (n=548) Clarithromycin 250 mg by mouth every 12 hours (n=537) Linezolid 600 mg every 12 hours (n=1498) All Other Comparators Comparators included cefpodoxime proxetil 200 mg by mouth every 12 hours; ceftriaxone 1 g intravenously every 12 hours; dicloxacillin 500 mg by mouth every 6 hours; oxacillin 2 g intravenously every 6 hours; vancomycin 1 g intravenously every 12 hours. (n=1464) Headache 8.8 8.4 5.7 4.4 Diarrhea 8.2 6.1 8.3 6.4 Nausea 5.1 4.5 6.6 4.6 Vomiting 2.0 1.5 4.3 2.3 Dizziness 2.6 3.0 1.8 1.5 Rash 1.1 1.1 2.3 2.6 Anemia 0.4 0 2.1 1.4 Taste alteration 1.8 2.0 1.0 0.3 Vaginal moniliasis 1.8 1.3 1.1 0.5 Oral moniliasis 0.5 0 1.7 1.0 Abnormal liver function tests 0.4 0.2 1.6 0.8 Fungal infection 1.5 0.2 0.3 0.2 Tongue discoloration 1.3 0 0.3 0 Localized abdominal pain 1.3 0.6 1.2 0.8 Generalized abdominal pain 0.9 0.4 1.2 1.0 Of the patients treated for uSSSIs, 3.5% of linezolid-treated and 2.4% of comparator-treated patients discontinued treatment due to drug-related adverse events. For all other indications, discontinuations due to drug-related adverse events occurred in 2.1% of linezolid-treated and 1.7% of comparator-treated patients. The most common reported drug-related adverse events leading to discontinuation of treatment were nausea, headache, diarrhea, and vomiting. Pediatric Patients The safety of linezolid formulations was evaluated in 215 pediatric patients ranging in age from birth through 11 years, and in 248 pediatric patients aged 5 through 17 years (146 of these 248 were age 5 through 11 and 102 were age 12 to 17). These patients were enrolled in two Phase 3 comparator-controlled clinical trials and were treated…